Hexahydro-dibenzo[b,d]pyran-9-ones in treatment of glaucoma

ABSTRACT

Use of 1-hydroxy-3-alkyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones in treatment of glaucoma.

BACKGROUND OF THE INVENTION

1-Hydroxy-9-keto-3-alkyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans(preferably named as1-hydroxy-3-alkyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones)were synthesized as intermediates by Fahrenholtz, Lurie and Kierstead,J. Am. Chem. Soc., 88, 2079 (1966), 89 5934 (1967) according to thefollowing reaction procedure: a 5-alkyl resorcinol is reacted withdiethyl α-acetylglutarate to form an ethyl4-methyl-5-hydroxy-7-alkylcoumarin-3-propionate. Cyclization of thislactone ester with a metal hydride yields a tricyclic keto lactone ofthe following structure (Formula I): ##STR1## Protection of the 9-ketogroup by ketal formation followed by treatment of the ketal with amethyl Grignard Reagent and subsequent cyclization and removal of theketal group yields a1-hydroxy-3-alkyl-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-dibenzo[b,d]pyran-9-oneof Formula II below: ##STR2## Reduction of the Δ¹⁰(10a) double bond withlithium in liquid ammonia at -78° C. yields predominantly the transketone,dl-trans-1-hydroxy-3-alkyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,Formula III, along with minor quantities of the corresponding 6a,10a cisisomer. ##STR3## No pharmacological activity was reported for thiscompound and it was used only as an intermediate. Compounds according toFormula III can readily be transformed by treatment with a methylGrignard Reagent to the corresponding 9-methyl-9-hydroxy compound,dehydration of which yields directly either a Δ⁸ or Δ⁹-tetrahydrocannabinol derivative, the latter being an active constituentof hashish. The Fahrenholtz et al synthesis is also described in U.S.Pat. No. 3,507,885 and in U.S. Pat. No. 3,636,058, acontinuation-in-part of the previous patent. (In the Fahrenholtz et alpatents, structure VI corresponds to Formula I above, structure VII toFormula II above, and structure III to Formula III above). Althoughapparently only a single compound of Formula III above was actuallyprepared by Fahrenholtz (the 3-n-pentyl derivative -- see example 8 ofU.S. Pat. No. 3,636,058), a large number of alkyl substitutedresorcinols are described, all of which can be used to synthesize other3-alkyl derivatives of Formula III. Resorcinols named include5-(1,2-dimethylheptyl)resorcinol, 5-(1-methyloctyl)resorcinol,5-(1-methylheptyl)resorcinol, 5-(1,2-dimethylbutyl)resorcinol, etc.Petrzilka, U.S. Pat. No. 3,873,576 discloses a different procedure forpreparing Δ⁹ -T.H.C. which utilizes different intermediates from thoseemployed by Fahrenholtz et al. A review article "Problems of DrugDependence -- Cannabis (Marijuana) Selected Bibliography (1950-1967)prepared by the Medical Literature Branch, Bureau of Medicine, FDA,Department of Health, Education and Welfare, Addendum I, SubstancesOccurring Naturally in Marijuana, etc., Isbel, (Washington, D.C., 1968)"and an article entitled Recent Advances in the Chemistry of Hashish,Mechoulam and Gaoni, Fortschritte Der Chemie Organicher Naturstoffe, 25,175 (Springer, Wien, 1957) mention the Fahrenholtz, et al synthesis aswell as other synthetic procedures for preparing activetetrahydrocannabinols; no pharmacological activity for compounds havinga ketone group at 9 in the dibenzopyran ring system is recorded therein.

Archer, U.S. Pat. No. 3,928,598 discloses the use as anti-anxiety,sedative, analgesic and antidipressant agents of compounds according toFormula IV below.

SUMMARY OF THE INVENTION

This invention provides a process for reducing the intraocular pressurein mammals which comprises administrating to a mammal having an abovenormal intraocular pressure an effective intraocular pressure reducingdose of a compound of Formula IV: ##STR4## wherein R' is either C₇ -C₁₀normal alkyl or is ##STR5## wherein R" is C₂ -C₇ alkyl, R^(v) is H ormethyl, R"' is hydrogen or C₁ -C₄ alkanoyl, and wherein both R groupsare the same and can be hydrogen or methyl. The process of thisinvention is potentially useful in the treatment of glaucoma in humans.Pharmaceutical compositions in unit dosage form Useful for reduction ofintraocular pressure consist of a pharmaceutical carrier and, as atherapeutic agent, from 0.1 to 25 mg. of a compound of Formula IV. The == = = = = = = = = = = dosage form may be given one to six times daily,yielding a daily dosage in the range of 0.1 to 100 mgs. of a compound ofstructure IV with the preferred daily dosage being in the range 1-20 mg.

Illustrative of R' in Formula IV when it is C₇ -C₁₀ normal alkyl aren-heptyl, n-octyl, n-nonyl and n-decyl. Illustrative groups which R" canrepresent in the grouping ##STR6## are the following: ethyl, n-propyl,isopropyl, sec-butyl, n-butyl, isobutyl, iso-amyl, t-amyl, n-amyl2-pentyl, 3-pentyl, 3-methyl-2-butyl, 2-hexyl, 1-hexyl, 3-hexyl,4-methyl-1-pentyl, 3-methyl-1-pentyl, 3-methyl-2-pentyl, neopentyl,3,3-dimethyl-1-butyl, 3,3-dimethyl-1-pentyl and the like groups. Thusgroups illustrative of R', when it is the above moiety are thefollowing: 1,2-dimethylheptyl, 1,1-dimethylheptyl, 1,2-dimethylhexyl,1,1-dimethylpentyl, 1,1-dimethylpropyl, 1-methylbutyl, 1-methyloctyl,1-methylheptyl, 1-methylhexyl and the like. The term C₁ -C₄ alkanoylwhich R"' can represent includes acetyl, propionyl, n-butyryl andisobutyryl.

The following hexahydrodibenzopyranones illustrate the scope of FormulaIV above for compounds useful in the processes and compositions of thisinvention.

1-Acetoxy-3-n-heptyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]-pyran-9-one,1-hydroxy-3-(1'-methyl-2'-butenyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-propionoxy-3-(1'-methylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-hydroxy-3-(1',1'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-butyroxy-3-(1',2'-dimethylpentyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-hydroxy-3-(1',1'-dimethyl-2'-butyl)-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-hydroxy-3-n-heptyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-hydroxy-3-(1',1'-dimethylhexyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-acetoxy-3-n-heptyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo-[b,d]pyran-9-one,

1-hydroxy-3-(1'-methyl-2'-butyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-propionoxy-3-(1'-methylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-hydroxy-3-(1',1'-dimethylhexyl)-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,

1-n-butyroxy-3-(1',1'-dimethylpentyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,and

1-acetoxy-3-(1',1'-dimethyl-2'-butyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.

The compounds of this invention in which both R groups in the 6-positionof Formula IV are methyl are prepared according to the procedure ofFahrenholtz et al referred to above. In this procedure, an alkylresorcinol is condensed with a dialkyl α-acetoglutarate followed bycyclization with sodium hydride in DMSO to yield a compound according toFormula I above which, after initial formation and reaction with aGrignard Reagent followed by treatment with 6N acid, yields a10,10a-dehydro-9H-dibenzo[b,d]pyran of Formula II above. Reduction ofthe Δ¹⁰(10a) double bond then yields dimethyl compounds according toFormula III.

Compounds in which both R groups attached to C₆ are hydrogen in FormulaIV are prepared according to the following general procedure: The ketonegroup of a keto-lactone according to Formula I above is reacted withethylene glycol to form the corresponding 9-ketal. Reduction of theketal with sodium bismethoxyethoxyaluminum hydride in benzene yields a2-(2'-hydroxymethyl-5'-ethylenedioxy-Δ¹ -cyclohexenyl)-5-alkylresorcinol of formula V. ##STR7##

On work-up in acidic medium, the ketal protecting group is removed and acompound of Va is actually isolated. ##STR8##

Treatment of this resorcinol (Va) with aluminum oxide in benzenecyclizes the compound to yield a derivative which, upon hydrogenation bythe procedures of U.S. Pat. No. 3,507,885--either lithium, sodium, orpotassium in liquid ammonia or hydrogenation over Raney nickel at ahydrogen pressure in the range 100-5,000 psi--yields adibenzo[b,d]pyran-9-one according to Formula III above in which both Rgroups attached to C₆ are hydrogen.

Compounds according to formula IV above contain asymmetric centers at 6aand 10a. In addition, there may be asymmetric centers in the side-chainalkyl group as, for example, when R' is 1,2-dimethyl heptyl, twoasymmetric centers are present in this side-chain. The Fahrenholtzsynthetic procedure described above in which the double bond isomerizesfrom the Δ^(6a)(10a) position to the Δ¹⁰(10a) position produces aracemate in which C_(6a) is asymmetric, the hydrogen being either aboveor below the plane of the dibenzopyran fused-ring system. Hydrogenationof the Δ¹⁰(10a) double bond with, for example, an active metal in liquidammonia produces a second asymmetric center at C_(10a), but the hydrogenwhich adds to this carbon under the hydrogenation or reductionconditions will usually take the more favorable trans configurationrelative to the hydrogen at C_(6a) with a lesser quantity of compound ofthe cis configuration being produced. Thus, synthesis of a compound inwhich the side chain contains no asymmetric centers, as for example,1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,will result in two racemates or racemic pairs in which the transracemate predominates. Compounds such as1-hydroxy-3-(1',2'-dimethylheptyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-onecontaining two asymmetric centers in the side chain will have a total offour asymmetric centers, those at 6a, 10a and at C₁ -- and C₂ -- in theside chain, yielding altogether 16 possible isomers occuring as 8racemates.

The resorcinol starting materials useful in the Fahrenholtz synthesissuch as n-hexyl resorcinol are readily available from the art.Resorcinols with a doubly branched alkyl group in the 5-position can beprepared by the procedure of Adams et al., J. Am. Chem. Soc., 70, 664(1948). These α,α-branched 5-alkylresorcinols are in general produced bydoubly alkylating a 3,5-dimethoxyphenylacetonitrile, converting thenitrile group to a ketone, reducing the ketone carbonyl to an alcohol,dehydrating the alcohol and then hydrogenating the resulting doublebond. Demethylation then yields a 5-(1',1'-dimethylalkyl)resorcinol.Resorcinols having an alkyl side chain with an α,β-substitution patternare in general prepared from 3,5-dimethoxybenzamide. Conversion of thebenzamide to a ketone using the appropriate Grignard Reagent followed bythe action of a methyl Grignard Reagent on the resulting ketone yields atertiary carbinol. Dehydration of the carbinol produces an ethyleniccompound which on hydrogenation yields a 3,5-dimethoxy-(α,β-substitutedalkyl)benzene. This latter compound is readily demethylated to form thecorresponding 5-(1'-methyl-2'-alkyl-substituted alkyl)resorcinol.5-alkyl resorcinols lacking an α branch can be prepared by standardmethods available in the art, including the reaction of a nitrile with aGrignard Reagent followed by reduction of the resulting carbonyl,dehydration of the thus formed benzylic alcohol and hydrogenation toyield an alkyl group, or by hydrogenolysis of a benzylic alcoholdirectly.

The synthesis procedure used for preparing compounds useful in theprocesses and compositions of this invention is illustrated by thefollowing specific example:

EXAMPLE 1 Preparation of1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one

A mixture containing 114 g. of 5-(1',1'-dimethylheptyl)resorcinol, 112g. of diethyl 2-acetylglutarate and 74 g. of phosphorous oxychloride wasstirred at ambient temperature for about 10 days. The reaction mixturewas then dissolved in ethyl acetate and the ethyl acetate layer washedseveral times with an equal volume of water until the water wash wasneutral to litmus. The organic layer was separated and dried, and thesolvent removed by evaporation in vacuo. The residue, comprising ethyl7-(1',1'-dimethylheptyl)-5-hydroxy-4-methyl-2-oxy-2H-1-benzopyran-3-propionateformed in the above reaction, was purified by chromatography over 2 kg.of neutral alumina using chloroform as the eluant. 142 g. of purifiedproduct thus obtained, were dissolved in 300 ml. of DMSO(dimethylsulfoxide), and the solution added in dropwise fashion to asuspension of 33.6 g. of sodium hydride in 100 ml. of DMSO. After theaddition had been completed, the reaction mixture was allowed to standat ambient temperature overnight. Excess sodium hydride present wasdecomposed by the dropwise addition of ethanol. The reaction mixture wasnext carefully poured over a mixture of ice and 12 N aqueoushydrochloric acid. A solid resulted comprising3-(1',1'-dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9(8H)-dione,which was collected by filtration. The solid filter cake was dissolvedin methyl ethyl ketone and the resulting solution washed with 5 percentaqueous sodium bicarbonate followed by saturated aqueous sodiumchloride. The organic layer was dried, and the solvent removed byevaporation in vacuo. Trituration of the crude residue with anhydrousether followed by filtration (the filtrate being discarded) yieldedabout 92.6 g. of a light yellow solid. 3-(1',1'-Dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9(8H)-dionethus obtained was used in its semi-purified state. A solution of 2.3 g.of the above product in 125 ml. of benzene also containing 2.5 ml. ofethylene glycol and 5 mg. of p-toluenesulfonic acid was heated overnightunder reflux using a water collector. After cooling, the reactionmixture was poured into 5 percent aqueous sodium bicarbonate. Theorganic layer was separated, washed with water and then dried. Removalof the organic solvent in vacuo yielded 2.5 g. of3-(1',1'-dimethylheptyl)-7,8-dihydro-1-hydroxyspiro[9H-dibenzo[b,d]pyran-9,2'-[1,3]-dioxolan]-6(10H)-one.This product was also used without purification.

A solution of the product in 50 ml. of anhydrous ether was addeddropwise to 46 ml. of a 2.8 M methyl Grignard Reagent in anhydrousether. After the addition had been completed, the reaction mixture wasrefluxed overnight, cooled, and then carefully poured into an ice and 6Naqueous hydrochloric acid mixture. Evaporation of the ether by heatingon a steam bath yielded a light yellow precipitate which was collectedby filtration. The solid material was washed several times with ether togive 1.64 g. of a light yellow solid comprisingdl-3-(1',1'-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]-pyran-9-one;MP = 194°-196° C.

Rf=0.26 (silica gel, 20% ethyl acetate:benzene): UV (ethanol) λ_(max)207/230/323 mμ (ε=25,600/13,200/23,200);

Ir(chloroform) 6.1μ (C═O); NMR (CDCl₃)

δ7.4 (d/J=2 cps/1H/H₁₀), δ6.46/6.26(2d/J=2 cps/2H/H₂ and H₄),

δ1.21(s/6H/gem dimethyl at C-1') and δ9.83ppm (t/3H/ω-methyl);

molecular ion; m/e=370.

A solution of 1.5 g. ofdl-3-(1',1'-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]-pyran-9-onein 50 ml. of anhydrous tetrahydrofuran (THF) was added dropwise to asolution of lithium metal in liquid ammonia at -80° C. Excess lithiummetal was added in chunks to the solution as the blue color, indicatingfree dissolved lithium, disappeared. After the addition was complete,ammonium chloride was added to react with any excess lithium metal stillpresent. The mixture was then allowed to warm to room temperature in anitrogen atmosphere during which process the ammonia evaporated. Thereaction mixture was then acidified with 1N aqueous hydrochloric acid,and the organic constituents extracted with ethyl acetate. The ethylacetate extracts were combined, washed with water and dried. Evaporationof the ethyl acetate under reduced pressure yielded 1.4 g. of crudedl-trans-3-(1',1'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.The crude product was chromatographed over 50 g. of silica gel frombenzene solution and the desired product was eluted in 20 ml. fractionswith a benzene eluant containing 2 percent ethyl acetate. Fractions200-240 contained 808 mg. of a white crystalline solid comprisingpurifieddl-trans-3-(1',1'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.The purified compound melted at 159°-160° C. after recrystallizationfrom an ethyl acetate-hexane solvent mixture. R_(f) =0.45 (silica gel,20% ethyl acetate:benzene).

Uv(ethanol) λmax 207/280mμ (ε=47,000/250); IR(CHCl₃) 5.85 μ(C═O); NMR(CDCl₃) δ7.75(s/1H/exchanges with D₂ O), δ6.36/6.34 (2d/J=2 cps/2H/H₂and H₄), δ4.15(d broad/J=14,3 cps/1H/H₁₀α), δ3.08-0.7 (multiplet/32H),especially δ1.47/1.13 (2s/each 3H/6α and 6β CH₃), δ1.21(s/6H/gem-dimethyl at C-1') and δ0.83 ppm (t/3H/ω-methyl); molecularion, m/e 372.

Anal. Calcd. for C₂₄ H₃₆ O₃ : C, 77.38; H, 9.74; O, 12.88 Found: C,77.59; H, 9.68; O, 12.99.

dl-cis-3-(1',1'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-onewas prepared by further elution of the above chromatographic column withbenzene containing 5 percent ethyl acetate. 140 mg of a whitecrystalline solid consisting ofdl-cis-3-(1',1'-dimethylheptyl)-6,6a-7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-onehaving the following physical and chemical characteristics: m.p. =151°-153° C;

R_(f) 0.38(Silica Gel, 20% EtOAc-benzene); NMR (CDCl₃)δ6.98(s/1H/exchanges with D₂ O), δ6.36(s broad/2H/H₂ and H₄), δ1.40,1.35(2s/each 3H/6α and 6β CH₃), δ1.20 (s/6H/gem dimethyl at C-1') andδ0.83 ppm (t/3H/ω-methyl); molecular ion, m/e 372

Anal. Calcd. for C₂₄ H₃₆ O₃ : C, 77.38; H, 9.74; O, 12.88 Found: C,77.61; H, 10.00; O, 12.57.

Other compounds preparable by the above procedure include:

dl-trans-3-(1',2'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-onehaving the following physical and chemical characteristics:

m.p. 119°-120° C; R_(f) =0.68 (silica gel, 20% ethyl acetate:benzene);UV(C₂ H₅ OH) λmax 208/280mμ (ε=48,400/800); IR (CHCl₃) 5.85μ (C═O); NMR(CDCl₃) δ6.30 (brs/2H/aromatics); δ4.23(d broad/J=14.0, 3.0cps/1H/H₁₀α); δ1.50/1.15 (2s/each 3H/6α and 6β CH₃) and δ0.82ppm(t/3Hω-methyl); molecular ion, m/e=372.

Anal. Calcd. for C₂₄ H₃₆ O₃ : C, 77.38; H, 9.74; O, 12.88 Found: C,77.67; H, 9.98; O, 13.00.

dl-trans-3-n-heptyl-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-onehaving the following physical and chemical characteristics: m.p.116°-117° C; R_(f) =0.38 (Silica gel, 20% ethyl acetate:benzene);UV(C₂H₅ OH) λmax 208.280mμ (ε=12,000/600); IR (CHCl₃) 5.87 μ (C═O); NMR(CDCl₃ δ7.95 (s/1H/exchanges with D₂ O), δ6.30(s broad/2H/H;hd 2 andH₄), δ4.22 (broad d/J = 14.0, 3.0/1H/H₁₀α), δ1.30/1.12(2s/each 3H/6αand6β CH₃) and δ0.87 ppm (t/3H/ω-methyl): molecular ion, m/e = 344.

Anal. Calcd. for C₂₂ H₃₂ O₃ : C, 76.70; H, 9.36; O, 13.93 Found: C,76.80; H, 9.12; O, 13.68.

dl-trans-1-hydroxy-3-(1'-methylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-onewith these characteristics: m.p. 137°-138° R_(f) 0.36 (Silica gel, 20%ethyl acetate:benzene); UV(EtOH) 208/280 mμ (ε=48,800/400); IR(CHCl₃)5.86 μ (C═O); NMR (CDCl₃) δ7.8(s/1H/exchanges with D₂ O), δ6.32(2H/H₂and H₄), δ4.20 (d broad/J=14/3 cps/1H/H₁₀α), δ1.48/1.13(2s/each 3H/6αand 6β CH₃), δ1.23(s/6H/gem dimethyl at C-1') and δ0.83ppm(t/3H/ω-methyl); high resolution mass spec confirms MW = 358 andempirical formula C₂₃ H₃₄ O₃.

Other compounds preparable by the above procedure and useful in theprocesses of this invention include:

dl-trans-1-hydroxy-3-(1',1'-dimethylpentyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one

dl-trans-1-hydroxy-3-(1',1'-dimethylpropyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one

dl-trans-1-hydroxy-3-(1',1'-dimethyloctyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one

The 1-acetoxy derivatives according to the Formula IV in which R'" is C₁-C₄ lower alkanoyl are prepared by reacting a compound in which R'" ishydrogen with a lower alkanoyl chloride or anhydride.

EXAMPLE 2 Preparation ofdl-trans-1-acetoxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one:

A mixture of 500 mg. ofdl-trans-1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,5 ml. of acetic anhydride, and 5 ml. of pyridine was stirred under aninert atmosphere for 16 hours. The mixture was then poured onto ice andextracted with ethyl acetate. The ethyl acetate extract was washed with1 N HCl and saturated sodium chloride solution, dried over anhydroussodium sulfate and evaporated in vacuo to give 450 mg. ofdl-trans-1-acetoxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-oneas a viscous oil: R_(f) =0.33(Silica gel, 10% Ethyl acetate:benzene): IR(CHCl₃) 5.62, 5.80, and 8.28 μ; molecular ion at m/e 414.

As previously mentioned, compounds represented by Formula IV above havethe ability to reduce intra-ocular pressure in mammals and thus arepotentially useful in the treatment of glaucoma in humans. The compoundsof Formula IV when so employed avoid most of the side-effects associatedwith presently used anti-glaucoma agents, such immediate side-effectsincluding headache and blurred vision. After systemic absorption,bradycardia and hypertension may also develop. Lenticular opacities alsodevelop frequently with prolonged use of long-acting acetylcholinesterase inhibitors, etc. frequently encountered with the use ofcholinergic or anti-cholinesterase compounds.

Compounds within the scope of Formula IV above and are active inreducing intraocular pressure includedl-trans-1-hydroxy-3-(1',2'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,dl-cis-1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,dl-trans-1-hydroxy-3-(1'-methylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,dl-trans-1-hydroxy-3-(n-heptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,dl-trans-1-hydroxy-3(1',1'-dimethylpentyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,dl-trans-1-hydroxy-3-(1',1'-dimethylpropyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one,dl-trans-1-hydroxy-3-(1',1'-dimethyloctyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9one,anddl-trans-1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.

Compounds represented by Formula IV above can be administered to mammalswith elevated intraocular pressure by either the oral, intraocular orparenteral route, the oral route being preferred. The compounds arerelatively insoluble and in preparing any pharmaceutical form containingthem it is desirable that the compound be in a finely divided state suchas that obtainable after rapid evaporation of a solution of the drug. Inaddition, aqueous suspensions of the drug should be used as soon aspossible after being prepared, and the suspension concentrate should bemaintained in the dry state until use since it has been found that, uponstanding in solution, the compound which was originally in a finelydivided state may slowly crystallize to a less absorbable form.Preferably, a polymorphic form of the drug, prepared by rapidly addingan ethanolic solution thereof to a large quantity of water, as set forthin the copending application of Arvind L. Thakkar, Ser. No. 413,011,filed Nov. 5, 1973 now abandoned, and in continuation-in-partapplication of Thakkar Ser. No. 504,391 filed Sept. 11, 1974, nowabandoned, in continuation-in-part application Ser. No. 628,251, filedDec. 8, 1975, of Thakkar, now abandoned and in continuation-in-partapplication of Thakkar, Ser. No. 707,786 filed July 22, 1976 should beused. The polymorphic form thus prepared is stable and readilyabsorbable, giving satisfactory drug blood levels after oraladministration. it does not revert (probably by recrystallization) toless absorbable crystalline forms on standing for periods of time up totwo weeks or longer.

An aqueous suspension of a drug represented by Formula IV is prepared asfollows: An acetone solution containing 2 parts of weight of, forexample1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-oneis mixed with 1 part by weight of aqueous polyoxyethylenesorbitanmonooleate. The solution is placed in a glass ampoule and the acetoneevaporated in vacuo. Just before use, 100 parts by weight of water areadded giving a final concentration of 2 mg/ml.

Capsules containing drug according to formula IV above suitable for usein the processes of this invention can be prepared as follows: 1 part ofweight of drug (obtained by adding an ethanol solution thereof rapidlyto a large volume of water and then collecting the precipitate) is mixedwith 9 parts of starch and the mixture loaded into empty telescopinggelatin capsules such that each capsules contains 10 mg of drug and 90mg. of starch. Alternatively, a mixture containing 10 parts of drug fromacetone solution, 1 part of polyoxyethylenesorbitan monooleate orsimilar suitable surfactant and 89 parts of starch are thoroughly mixedand placed in empty telescoping gelatin capsules such that each capsulewill contain 10 mg. of drug. Solutions of compounds according to theabove formula for use in oral administration can be prepared in anydesired strength in polyethyleneglycol 300 (N.F.). In addition, drugsaccording to Formula IV above in absorbable polymorphic form can becompounded into scored tablets containing from 0.4 to 100 mg of drug pertablet, along with other standard ingredients used in preparing tabletssuch as starch, a lubricants and binders.

One preferred mode of administration of a dibenzo[b,d]pyran-9-oneaccording to Formula IV above is in the form of a dispersion withpolyvinylpyrrolidone or with polyethylene glycol (PEG) as taught in thecopending application of Arvind L. Thakkar, Ser. No. 413,012, filed Nov.5, 1973, now U.S. Pat. No. 3,920,809 issued Nov. 18, 1975. In accordancewith the teachings of Thakkar, a polyvinylpyrrolidone (PVP) complex isformed with the active drug having a structure of Formula IV above, forexample1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.In preparing the complex, a solution of 90 parts of PVP dissolved inethanol is mixed with an ethanol solution containing 10 parts of drug,and the ethanol is evaporated therefrom in vacuo. The resulting solid isthen mixed with 89 parts of starch and 1 part of polyoxyethylenesorbitanmonooleate, and the mixture loaded into an empty telescoping gelatincapsules such that each capsule contains 5 mg. of drug. An alternativepharmaceutical preparation is available for treatment of glaucoma; i.e.,a form which permits topical administration of a drug according toFormula IV directly to the mammalian eye. The lack of water solubilityof compounds according to Formula IV somewhat limits the availability ofsuch forms for use in the process of this invention. A particularlyuseful form for introduction directly to the eye are the PVP and PEGcomplexes of Thakkar, referred to above. These complexes can bedispersed in aqueous solution. For example, a complex of 5 parts of1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo(b,d)hexan-9-one,45 parts of PEG (MW = 3000) and one-half part of a surfactant such aspolyoxethylenesorbitan monooleate is diluted with sufficient water togive final concentration of 5 mg. of drug per ml. Such a formulation canbe applied directly to the eye. Other forms useful for deliveringmedication directly to the eye include solid formulations placed in thecul-de-sac of the conjunctiva (as illustrated in U.S. Pat. Nos.3,870,791 and 3,868,445). The Opthalmology Prescription Handbook, 1stEd. (E. J. Browning Medical Publications, Inc. Pasadena, Cal. 1964)contains information as to other similar pharmaceutical formulations foruse in applying medicaments to the eye adaptable to the compounds ofFormula IV.

As will be understood by those versed in the art, it is possible to varythe amount of drug in each of the above dosage forms so that unit dosagewill contain from 0.1 to 25 mg. of drug with final daily dosages of from0.1 to 100 mg/patient.

We claim:
 1. A process for reducing intraocular pressure in mammalswhich comprises administering to a mammal with an elevated intraocularpressure an intraocular pressure reducing dose of a compound representedby the formula ##STR9## wherein R' is either C₇ -C₁₀ normal alkyl or isthe group ##STR10## wherein R" is C₂ -C₇ alkyl and R^(v) is H or methyl,wherein both R groups are identical and are H or methyl and wherein R'"is H or C₁ -C₄ alkanoyl, in an amount effective to releive intraocularpressure.
 2. A process according to claim 1 in which a dose of from 0.1to 100 mgs per day of the drug is administered.
 3. A process accordingto claim 1 in which a dose of from 1 to 20 mgs. per day of the drug isadministered.
 4. A process according to claim 1 in which the drug isadministered by the oral route.
 5. A process according to claim 1 inwhichdl-trans-1-hydroxy-3-(1',1'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-6,6-dimethyl-9H-dibenzo[b,d]pyran-oneis administered.
 6. A process according to claim 1 in whichdl-trans-1-hydroxy-3-(1',2'-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-oneis administered.
 7. A process according to claim 1 in whichdl-trans-1-hydroxy-3-(1'-methylheptyl)-6,6a,7,8,10,10a-hexahydro-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-oneis administered.
 8. A process according to claim 1 in which the drug isadministered topically to the eye.